METHOD FOR THE TREATMENT OF ATHEROSCLEROSIS, THROMBOSIS AND PERIPHERAL VESSEL DISEASE

METHODE DE TRAITEMENT DE L'ATHEROSCLEROSE, DE LA THROMBOSE ET DES MALADIES DES VAISSEAUX PERIPHERIQUES

English Abstract

-1- HOE 85/F 229
Abstract of the Disclosure:
The invention relates to a method for the treatment of
atherosclerosis, thrombosis and/or of peripheral vessel
disease by administration of angiotensin converting
enzyme inhibitors. Administration of compounds of the
formula I
<IMG> (I)
in which n is 1 or 2, R, R1, R2 and R3 are identical
or different and each denotes hydrogen or an organic
radical, and R4 and R5 form, together with the atoms
carrying them, a mono-, bi- or tricyclic heterocyclic
ring system, is preferred. The invention also relates
to angiotensin converting enzyme inhibitors and to
agents containing them for administration for the
treatment of the abovementioned diseases.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. An angiotensin converting enzyme inhibitor of the formula
I
<IMG> (I)
in which
n is 1 or 2,
R = hydrogen, an aliphatic radical having 1-8 carbon atoms,
an alicyclic radical having 3-9 carbon atoms, an aromatic
radical having 6-12 carbon atoms, an araliphatic radical
having 7-14 carbon atoms, an alicyclic-aliphatic radical
having 7-14 carbon atoms, or a radical ORa or SRa, in
which Ra represents an aliphatic radical having 1-4
carbon atoms, an aromatic radical having 6-12 carbon
atoms, or a mono- or bicyclic heteroaryl which may be
partially hydrogenated and which has 5 to 7 or 8 to 10
ring atoms, respectively, 1 or 2 of these ring atoms
representing sulfur or oxygen atoms and/or 1 to 4 of
these ring atoms representing nitrogen atoms,
R1 denotes hydrogen, an aliphatic radical having 1-6 carbon
atoms, an alicyclic radical having 3-9 carbon atoms, an
alicyclic-aliphatic radical having 4-13 carbon atoms, an
aromatic radical having 6-12 carbon atoms, an araliphatic
radical having 7-16 carbon atoms, mono- or bicyclic
heteroaryl which may be partially hydrogenated and which
has 5-7 or 8-10 ring atoms, respectively, 1 or 2 of these
ring atoms representing sulfur or oxygen atoms and/or 1
to 4 of these ring atoms representing nitrogen atoms/ or
the side chain, protected where necessary of a naturally
occurring .alpha.-amino acid,

R2 and R3 are identical or different and denote hydrogen,
an aliphatic radical having 1-6 carbon atoms, an
alicyclic radical having 3-9 carbon atoms, an aromatic
radical having 6-12 carbon atoms, or an araliphatic
radical having 7-16 carbon atoms, and
R4 and R5 form, together with the atoms carrying them, a
mono-, bi- or tricyclic heterocyclic ring system having
4 to 15 carbon atoms, or it physiologically tolerated
salt, for use in the treatment of one or more of
atherosclerosis, thrombosis and peripheral vessel disease
in mammals.
2. An angiotensin converting enzyme inhibitor of the formula
I as claimed in claim 1 in which R4 and R5 together with the
atom carrying them represent a system which may be
substituted, from the series comprising
tetrahydroisoquinoline, decahydroisoquinoline,
octahydroindole, octahydrocyclopentalb]pyrrole, 2-
azaspiro[4.5]decane, 2-azaspiro[4.4]nonana,
sprio [(bicyclo [2.2.1] heptane )-2, 3'-pyrrolindine],
spiro[bicyclo[2.2.2]octane)-2,3'-pyrrolidine], 2-
azatricyclo[4.3Ø16,9]decane, decahydrocyclohepta[b] pyrrole,
octahydroisoindole, octahydrocyclopenta[c]pyrrole,
2,3,3a,4,5,7a-hexahydroindole and 2-azabicyclo[3.1.0]hexane,
for use in the treatment of one or more of atherosclerosis,
thrombosis and peripheral vessel disease in mammals.
3. An angiotensin converting enzyme inhibitor of the formula
I as claimed in claim 1 in which
26

n is 1 or 2,
R denotes hydrogen, alkyl having 1-8 carbon atoms,
alkenyl having 2-6 carbon atoms, cycloalkyl having 3-9
carbon atoms, aryl which has 6 - 12 carbon atoms and
can be mono-, di- or trisubstituted by (C1-C4)-alkyl,
(C1-C4)-alkoxy, hydroxyl, halogen, nitro, amino,
aminomethyl, (C1-C4)-alkylamino, di-(C1-C4)-alkylamino,
(C1-C4)-alkanoylamino, methylenedioxy, carboxyl, one or
both of cyano and sulfamoyl, alkoxy having 1-4 carbon
atoms, aryloxy which has 6-12 carbon atoms and can be
substituted as described above for aryl, mono- or
bicyclic heteroaryloxy which has 5-7 or 8-10 ring
atoms respectively, 1 to 2 of these ring atoms
representing sulfur or oxygen atoms and/or 1 to 4 of
these ring atoms representing nitrogen atoms, and
which can be substituted as described above for
aryl, amino-(C1-C4)-alkyl, (C1-C4)-alkanoylamino-(C1
C4)-alkyl, (C7-C13)-aroylamino-(C1-C4-alkyl, (C1-
C4)-alkoxycarbonylamino-(C1-C4)alkyl, (C6-C12)-
aryl-(C1-C4)-alkoxycarbonylamino-(C1-C4)-alkyl,
(C6-C12)-aryl-(C1-C4)-alkylamino-(C1-C4)-alkyl,
(C1-C4)-alkylamino-(C1-C4)-alkyl, di-(C1-C4)-alkyl-
amino-(C1-C4)-alkyl, guanidino-(C1-C4)-alkyl,
imidazolyl, indolyl, (C1-C4)-alkylthio, (C1-C4)-
alkylthio-(C1-C4)-alkyl, (C6,-C12)-arylthio-(C1-C4)-
alkyl which can be substituted in the aryl moiety
as described above for aryl, (C6-C12) aryl-(C1-
C4)-alkylthio which can be substituted in the aryl
moiety as described above for aryl, carboxy-(C1-
C4)-alkyl, carboxyl, carbamoyl, carbamoyl-(C1-C4)-
alkyl, (C1-C4)-alkoxycarbonyl-(C1-C4)-alkyl, (C6-
C12)-aryloxy-(C1-C4)-alkyl which can be substitu-
ted in the aryl moiety as described above for
aryl, or (C6-C12-aryl-(C1-C4)-alkoxy which can
be substituted in the aryl moiety as described
above for aryl,
27

R1 denotes hydrogen, alkyl having 1-6 carbon atoms,
alkenyl having 2-6 carbon atoms, alkynyl having 2-6
carbon atoms, cycloalkyl having 3-9 carbon atoms,
cycloalkenyl having 5-9 carbon atoms, (C3-C9)-
cycloalkyl-(C1-C4)-alkyl, (C5-C9-cycloalkenyl-
(C1-C4)-alkyl, aryl which may be partially hydrogenated
which has 6-12 carbon atoms and can be substi-
tuted as described above for R, (C6-C12)-aryl-(C1-
C4)-alkyl or (C7-C13)-aroyl-(C1 or C2)-alkyl, both of
which can be substituted as the abovementioned aryl,
mono- or bicyclic, heteroaryl which may be partially
hydrogenated which has 5-7 or 8-10 ring atoms
respectively, 1 to 2 of these ring atoms representing
sulfur or oxygen atoms and/or 1 to 4 of these
ring atoms representing nitrogen atoms, and which can be
substituted as the abovementioned aryl, or the side
chain of a naturally occurring .alpha. -amino acid
R1-CH(NH2)-COOH, which may be protected
R2 and R3 are identical or different and denote hydro-
gen, alkyl having 1-6 carbon atoms, alkenyl having
2-6 carbon atoms, di-(C1-C4)-alkylamino-(C1-C4)-
alkyl, (C1-C5)-alkanoyloxy-(C1-C4)-alkyl, (C1-C6,)-
alkoxycarbonyloxy-(C1-C4)-alkyl, (C7-C13)-aroyloxy-
(C1-C4)-alkyl, (C6-C12)-aryloxycarbonyloxy-(C1-C4-
alkyl, aryl having 6-12 carbon atoms, (C6-C12)-
aryl-(C1-C4)-alkyl, (C3-C9)-cycloalkyl or
(C3-C9)-cycloalkyl-(C1-C4)-alkyl, and
R4 and R5 are defined as in claim 1, for use in the
treatment of one or more of atherosclerosis, thrombosis
and peripheral vessel disease in mammals.
28

4. [S,S,S,S,S]-N-carboethoxy-3-phenylpropyl)-alanyl-
octahydroindole-2-carboxylic acid, N-[1-(S)-carboethoxy-3-
phenylpropyl)-(S)-alanyl]-2s,3aR,7aS-octahydroindole-2-
carboxylic acid, [S,S,S,S,S]-N-[(1-carboethoxy-3-phenylpropyl)-
alanyl]-decahydroisoquinoline-3-carboxylic acid, [S,S,S]-
N-[(1-carboethoxy-3-phenylpropyl)-alanyl]-tetrahydroisoquinoline-
3-carboxylic acid, N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-
cis-endo-2-azabicyclo[3.1.0]hexane-3-S-carboxylic acid or
N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-cis-endo-2,3,3a,4,5,
7a-hexahydroindole-2-S-carboxylic acid for use in the treatment
of one or more of atherosclerosis, thrombosis and peripheral
vessel disease in mammals.
5. (S,S,S,S,S)-N-(1-carboethoxy-3-phenylpropyl)-alanyl-2-
azabicyclo[3.3.0] octane-3-carboxylic acid for use in the
treatment of one or more of atherosclerosis, thrombosis and
peripheral vessel disease in mammals.
6. The dicarboxylic acid of [S,S,S,S,S]-N-(1-carboethoxy-
3-phenylpropyl)-alanyl- octahydroindole-2-carboxylic acid,
N-[1-(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-2s,3aR,7aS-
octahydroindole-2-carboxylic acid, [S,S,S,S,S]-N-[(1-carboethoxy-
3-phenylpropyl)-alanyl]-decahydroisoquinoline-3-carboxylic acid,
[S,S,S]-N-[(1-carboethoxy-3-phenylpropyl)-alanyl]-tetrahydroiso-
quinoline-3-carboxylic acid, N-(1-S-carboethoxy-3-phenylpropyl)-
S-alanyl-cis-endo-2-azabicyclo[3.1.0]hexane-3-S-carboxylic acid
or N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-cis-endo-2,3,3a,4,
5,7a-hexahydroindole-2-S-carboxylic acid for use in the treatment
of one or more of atherosclerosis, thrombosis and peripheral
vessel disease in mammals.
29

7. The diacarboxylic acid of (S,S,S,S,S)-N-(1-carboethoxy-
3-phenylpropyl)-alanyl-2-azabicyclo[3.3.0]-octane-3-carboxylic
acid for use in the treatment of one or more of antherosclerosis,
thrombosis and peripheral vessel disease in mammals.
8. Use of a compound of the Formula I as defined in claim
2, 3 or 4 for use in the treatment of one or more of
atheroselerosis, thrombosis and peripheral vessel disease in
mammals.
9. Use of [S,S,S,S,S]-N-(1-carboethoxy-3-phenylpropyl)-
alanyl- octahydroindole-2-carboxylic acid, N-[1-(S)-
carboethoxy-3-phenylpropyl)-(S)-alanyl]-2s,3aR,7aS-octahydro-
indole-2-carboxylic acid, [S,S,S,S,S] N-[(1-carboethoxy-3-
phenylpropyl)-alanyl]-decahydroisoquinoline-3-carboxylic acid,
[S,S,S]-N-[(1-carboethoxy-3-phenylpropyl)-alanyl]-tetrahydro
isoquinoline-3-carboxylic acid, N-(l-S-carboethoxy-3-
phenylpropyl)-S-alanyl-cis-endo 2-azabicyclo[3.1.0]hexane-3-S-
carboxylic acid or N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-
eis-endo-2,3,3a,4,5,7a-hexahydroindole-2-S-carboxylic acid for
use in the treatment of one or more of atheroselerosis,
thrombosis and peripheral vessel disease in mammals.
10. Use of (S,S,S,S,S)-N-(1-carboethoxy-3-phenylpropyl)
-alanyl-2-azabicyclo-[3.3.0]-octane-3-carboxylic acid for use in
the treatment of one or more of atherosclerosis, thrombosis
and peripheral vessel disease in mammals.

11. Use of the dicarboxylic acid of
[S,S,S,S,S]-N-(1-carboethoxy-3-phenylpropyl)-alanyl-octahydro
indole-2-carboxylic acid, N-[1-(S)-carboethoxy-3-phenylpropyl)-
(S)-alanyl]-2s,3aR,7aS-octahydroindole-2-carboxylic acid,
[S,S,S,S,S]-N-[(1-carboethoxy-3-phenylpropyl)-alanyl]-decahydro-
isoquinoline-3-carboxylic acid, [S,S,S]-N-[(1-carboethoxy-3-
phenylpropyl)-alanyl]-tetrahydroisoquinoline-3-carboxylic acid,
N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-cis-endo-2-azabicyclo
[3.1.0]hexane-3-S-carboxylic acid or N-(1-S-carboethoxy-3-
phenylpropyl)-S-alanyl-cis-endo-2,3,3a,4,5,7a-hexahydroindole-2-S-
carboxylic acid for use in the treatment of one or more of
atherosclerosis, thrombosis and peripheral vessel disease in
mammals.
12. Use of the diacarboxylic acid of
(S,S,S,S,S)-N-(1-carboethoxy-3-phenylpropyl)-alanyl-2-azabicyclo
[3.3.0] octane-3-carboxylic acid for use in the treatment of one
or more of antherosclerosis, thrombosis and peripheral vessel
disease in mammals.
13. A pharmaceutical agent containing a compound of the
formula I as defined in any one of claims 1 to 7 or its
physiologically tolerated salt and a pharmaceutically
acceptable carrier, diluent or excipient, for
administration for the treatment of one or more of
atherosclerosis, thrombosis and peripheral vessel disease
in mammals.
31

Description

1 320qO~
A method for the treatnent of atherosclerosis, thro~-
bosis and peripheral vessel disease
The invention relates ~o a method for the treatment of
atheroscleros;s, o~ thrombosis and/or of peripheral
vessel dise~se by oral or parenteral ad~in;stration of
compounds which inhibit angiotensin converting enzyme.
S Particularly suitable for th;s purpose are compounds
of the formula I
~ l5 ~ o~2
in wh;ch
n ;s 1 or 2,
R - hydrogen, an optionally subst;tuted al;phatic
radical having 1-8 carbon atoms, an opt;onally sub-
stituted alicyclic radical having 3~9 carbon atoms,
an optionally substituted aromatic radical having
6-12 carbon atoms, an optionally substituted arali-
phati~ radical having 7-14 carbon atoms, an aption-
aLly substituted alicyclic-aliphatic radical having
7-14 rarbon atoms, or a radical ORa or SRa, in
which Ra represents an opticnally subs~i~uted
aliphatic radical having 1-4 c~rbon atoms, an opt-
ionally substituted aromatie radical having 6-12
carbon atoms, or an optionally substituted hetero-
aroma~ic radical having 5-12 ring atoms,
R denotes hydrogen, an optionally substituted ali-
phatic radical having 1-6 carbon atoms, an option-
ally substi~uted alicyclic radical having 3-9
carbon atoms, an optionally substituted alicyclic-
aliphatic radical having 4-13 carbon ato~s, an
optionally substituted aromatic radical having 6-12
carbon atoms, an option2lly ~ubstituted araliphat;c
radical havin~ 7-16 carbon atoms, an option3lly
substituted heteroaromatic radic~l having 5-12 r;ng

1 320904
-- 2 --
atoms, or the side chain, pro~ected where necessary,
of a naturally occurring ~-amino acid,
R2 and R3 are identical or different and denote hydro-
gen, an optionally substituted aliphatic radical
having 1-6 carbon atoms, an optionally substituted
alicyclic radical having 3 9 carbon atoms~ an opt-
ionally substituted aromatic radical having 6-12
carbon atoms, or an optionally subs~ituted aralipha-
tic radical having 7-16 carbon atoms, and
1D R4 and R5 form, together ~ith the ~toms carrying them,
a heterocyclic, mono-, bi- or ericyclic ring system
having 4 to 15 carbon atoms.
Particularly suitable ring systems of this type are
those of the following group:
Tetrahydroisoquinol;ne tA); decahydroisoquinoline (~j;
octahydroindoLe (C3; octahydrocyclopenta~b~pyrrole tD);
2-azaspiro~4.53decane (E); 2-azaspiroC4.4]nonane (F);
spirot(bicyclo~2.2.1~heptane)-2,3'-pyrrolidine~(G);
spiro~(bicyclo~2.2.2~octane)-2,3'-pyrrolidine~ tH);
2-azatricyclo~4.3Ø16,9]decane (I); decahydrocyclQ-
hepta~b]pyrrole (J); octahydroisoindole tK); octahydro-
cyclopentaZc~pyrrole (I); 2~3,3a,4,5,7a-hexahydroindole
(M); 2-azabicyclo~3.1.D~hexane (N); all of uhich can
optionally be substituted. However, the unsubs~ituted
Z5 systems ~re preferred.
In the case of compounds which have several chiral
ato~s, all possible diastereomers are suitabLe, as
racemates or enantiomers or ~ixtures of various dia-
st~reomers.
~he cycli~ amino acid esters ~hich are suitable have
the foLlo~ing structural formulae.

1 320qo4
-- 3
COOR3 ~ COOP~3
~ N~
A B ~N~LCOOR3
'~-C~'o~33_coo~3 3_,
'
G H
~) COOR3~COOR3 ~3_ 3
J . X L
~COOR3 ~COOR3
M N
A preferred embodiment compr;ses use of compounds of
the formula I in ~h;ch
n is 1 or 2~
R denot~s hydrogen, alkyl having 1-8 carbon atoms,
alkenyl hav;ng 2-6 carbon atoms, cycLoalkyl having
3-9 carbon atoms, aryL ~hich has 6-12 carbon at~ms
and can be ~ono-, di- or trisubsti~uted by (C1-C4)-
alkyl, (C1-C4)-alkoxy, hydroxyl, halogsn, nitro9
amino, amino~ethyl, (C1-C4)-alkylamino~ di-(C1-C4)-
, .
'

1 ;~20904
- 4 -
alkylamino, (C1-C4)-alkanoyl~mino, ~ethylenedioxy,
carboxyl, cyano and/or sulfamoyl, alkoxy having 1-4
carbon atoms~ aryloxy ~hich has 6-12 carbon atoms
and can be subs~i~uted as described above for aryl,
S mono- or bicyclic heteroaryloxy ~hich has 5-7 or 8-
10 ring atoms respectively, 1 to 2 of ~hese ring
atoms representing sulfur or oxygen a~oms and/or 1
to 4 of these ring atoms rPpresenting nitrogen, and
which can be substituted as described above for
aryl, amino-(C1-C~)-alkyl, (C1-C4)-alkanoylamino-tC1-
C4)-alkyl, (C7-C13)-aroylamino-(C1-C4)-alkyl, (C
C4)-alkoxycarbony~amino-tC1-C~)-alkyL, ~C6-S~
aryl-~C1-C4)-alkoxycarbonylamino-(C1-C4)-all(yl,
(C~,-C1~)-aryL-(Cl-C4)~alkylamino-(C1-C43-3lkyl,
(C1 C4)-alkyla~ino-(C1-C4)-alkyl, di-(C1-C4)-alkyl-
amino-(C1-C~)-alkyl, guanidino-(C~-C4)-alkyl,
imidazolyl, indolyl, (C1-C4)-alkylthio, (C1-C4)-
alkylthio-(C1-C4)-alkyl, (C~-C12)-arylthio (C1 C4
alkyl which can be substituted in the aryl moiety
as described above for aryl, (C6-C1z)-aryl-(C1-
C4~-alkyLthio ~hich can be su~stituted in the
aryl ~oi~ty as described ab~ve for aryl, carboxy-
(C~-C~3-alkyl, carboxyl, carbamoyl, carbamoyl-
~Cl-~4)-alkYl~ (c1-c4~-alkoxycarbonyl~ -c4)-
alkyl, (C6-C12)-aryloxy-(C1-C4)-alkyl ~hich can be
substituted in the aryl maiety as descr;bed above
for aryl, or (C6-C12)-aryl-(C1-C4~-alkoxy which can
be subs~ituted ir, the aryl moiety as described
above for aryl,
R denotes hydrogen~ alkyl having 1-6 carbon 3toms,
alkenyl having 2-6 carbon atomsy alkynyl having 2-6
carbon atoms, cycloalkyl having 3-9 carbon atoms~
cycloalkenyl having 5-9 c~rbon atoms, (C3~Cg)-
cycloalkyl-~C1-C4)-alkyl, (C~-Cg)-cyclo3lkenyl-
(C1-C43-alkyl, optionally partiaLly hydrogenated
aryl which has 6-12 carbon atoms and can be subst;
tuted as described above for R, Sr6-C1~)-aryl-(C1-
C43-alkyl or ~C7-C13)-aroyl (C1 or C23-alkyl, both

1 32nqo4
-- 5 --
of ~hich can be substituted as the abovementioned
aryl, mono- or bicyclic, op~ionally partially hydro-
genated heteroaryl which has 5-7 or 8-10 rin~ atoms
respectively, 1 or 2 of these ring atoms represent-
;ng sulfur or oxygen atoms and/or 1 to 4 of these
ring atoms representing nitrogen atoms, and ~hich
can be substituted as the abovementioned aryl, or
the optionally protected side chain of a naturally
occurring ~ am;no acid R1-CH(NH2) COOH~
R2 and R3 are identical or different and denote hydro-
gen, alkyl having 1-6 carbon a~oms, alkenyl having
2-6 carbon atoms, di-(C1-C4)-aLkyLam;no-(C1-C4)-
alkyL, tC1-Cs)-alkanoyloxy-(C1-C4)-alkyl, (C1-C6)-
alkoxycarbonyloxy-(C1-C4) alkyl, tC7-C13)-aroyloxy-
(C1-C4)-alkyl, (C6-C1z)-aryloxycarbonyloxy-(C1-C4)-
alkyl, aryl hav;ng 6-12 carbon atoms, (C6-C123-
aryl-(C1-C4)-alkyl, (t3-Cg)-cycloalkyl or
(C3~Cg)-cycloalkyl-(C1-C4~-alkyl, and
R4 and R5 have the abovement;oned meaning.
A particularly preferred embodimEnt romprises u~e of
compounds of the for~ula I in which
n is 1 or 2,
R denotes (C1-C6)-alkyl~ (C2-C6)-alkenyl, (C3-Cg)-
cycloalkyl, amino-(C1-C4)-alkyl, (Cz-Cs3-acylamino-
(C1-C4)-a~kYl~ (~7-c13)-aroylamino-tc1-c4)-alkyl~
(C1-C4)-alkoxycarbonylamino~(C1-C4)-alkyl9 (C6-tl2)
aryl-(Cl-C4)-alkoxycarbonylamino-(C~-C4)-alkyl,
tC6-C12)-aryl ~hich can be mono-, di- or trisub-
~tituted by ~C1-C4)-alkyl~ (C1-C4)-alkoxy, hydroxyl,
halogen, nitro~ am;no~ (C1-C4)-alkylamino, di-(C1-
C4)-alkylamino and/or methylened;oxy, or 3-indolyl,
in particular methyl, ethyl, cyclohexyl, tert.-
butoxycar~onyla~ino-(C1-C4~-alkyl, benzoyloxycarbon-
ylamino-(C1-C4)-alkyl, or phenyl ~hich can be mono-
or disubstituted, or in the case of methoxy tri-
substituted, by phenyl~ (C1-C2~-alkyl, tC1 or C23-
alkoxy, hydro~yl, fluorine~ chlorine, bromine,
amino, (t1-C4)-alkylamino, di-(C1-Cb)-alkylamino~

1 320904
)
nitro and/or methylened;oxy,
R1 denot~s hydrogen or (C1 C6)-alkyl which can option-
ally be substituted by amino, (C1-C6)-acylamino or
benzoylamino~ (C2-C6)-alkenyl, (C3-Cg)-cycloalkyl~
(Cs-Cg)-cycloalkenyl~ (C3-C7)-cycloalkyl-(~ 4)-
alkyl, (C6-C121-aryl or partially hydrogenated aryl,
each of which ean be substituted by (C1-Cb)-alkyl~
(C1 or C2)-alkoxy or halogen, (C6-C17~-aryl-(C1 to
C4)-alkyl or (C7-C13)-aroyl-(C1-C2)-alkyl, both of
which can be substituted in ~he aryl radical as de-
fined above, a mono- or b;cyclic heterocyclic
radical having 5 to 7 or 8 to 10 ring atoms respect-
ively, 1 ~o 2 of these ring atoms representing
sulfur or oxygen atoms andtor 1 to 4 of these ring
atoms representing nitrogen a~oms, or a side chain
of a naturally occurring, optionally protected
-amino acid, but in par~icular hydrogen, (C1-C3)-
alkyl, (C2 or C3)-alkenyl~ the opt;on3lly protected
side chain or lysine, benzyl, 4-methoxybenzyl, 4-
ethoxybenzyl, phenethyl, 4-aminobutyL or benzoyl-
methyl,
R2 and R3 denote identical or different rad;cals hydro-
gen, (C~-C6)-alkyl~ ~C2-C6)-alkenyl or (C6-C12)-
aryl-(C1-C~)-alkyl, but in particular hydrogen,
(C1-C4)-alkyl or benzyl, and
R4 and RS have the abovement;oned meaning.
It is particularly preferred to ~se compounds sf the
formula I in which
n is 2,
R denotes phenyl,
R1 denotes ~ethyl,
R2 and R3 denote identical or different (C1-C6)-alkyl
radicals or ~C7-C10)-araLkyL radicals such as benzyl
or nitrobenzyl, and
R4 and R5 together represent a radicaL of the for0ula

1 320904
-- 7 --
--lCH2
in ~hich
m denotes 0 or 1,
p denotes 0, 1 or ?, and
X denotes -CH2-, -CH2-CH2- or -CH=CH-, it also be;ng
possible for a 6-ring formed with X to be a ben-
zene ring.
In this context and in the following, aryL is to be
understood preferably to be substituted phenyl, bi-
phenylyl or naphthyl. A corresponding statement
applies to radicals derived from aryl, such as aryloxy
and arylthio. Aroyl is particularly understood to be
benzoylO Aliphatic radicals can be seraight-chain or
branched.
A mono- or bicyclic heterocyclic radical h3ving 5 to 7
or 2 to 10 ring atoms respectively, 1 to 2 of these
ring atoms representing sulfur or oxygen atQms andJor 1
to 4 of these ring ato~s representing nitrogen atoms~
is~to be understood to be~ for example, thienyLO benzo-
~b]thienyl, ~uryl~ pyranyl, benzofuryl, pyrroL~l, im;d-
azoLyl, pyrazolyl~ pyridyl, pyrimidinyl, pyridaz;nyl~
indazolyl, isoindolyl, indolyl, purinyl9 quinolizinyl,
isoquinolinyl, phthalazinyl, naph~hyridinyl, quinoxal-
inyl, quinazolyl, cinnolinyl, pteridinyl, ox~zolyl,
isoxazolyl, thiazolyl or isothiazolyl. These radicals
can also be part;ally or completely hydrogenated.
Naturally occurring ~-amino acids are described in~ for
example~ Houben-~eyl~ Methoden der Organischen Chemie
(Methods of Organic Chemistry)~ Vols. XV/1 and XVJ2.
~here R1 repr~sents a side ehain of a protected
naturally occ~rring ~ 3mino acid such as, for e~ample,

1 320qO4
protected Ser, Thr, Asp, Asn, Glu, GLn, Arg, Lys, Hyl,
Cys~ Orn, C;t, Tyr, Trp, H;s nr Hyp, the preferred pro-
tective groups are the ~roups customary in peptide
chemistry (ct. Houben-~eyl, Yols. XV/1 and XY/2)~ In
the case ~here R1 denotes the protected side chain of
lysine, the known a~ino protective groups, but in par-
ticular Z, Boc or ~C1-C6)-alkanoyl, are preferred.
Suitable and preferred as O-protective groups for tyro~
sine are ~C1-C6)-alkyl, in particular methyl or ethyl.
AC inh;bitors o~ the formuLa I can be prepared by
reacting together their fragments in a suitable sol-
vent, ~here appropriate in the presence of a base and/
or of a coupling auxiliary9 ~here appropriate reduction
of unsaturated compounds ~hich have resulted as inter-
mediates, such as Schiff's bases, and elimination ofprotective groups which have been introduced temporar-
ily to protect reactive groups and, ~here appropr;ate,
conversion of the resulting compounds into their physi-
ologically tolerated salts.
It is possible in the said manner to react rompounds of
the forMula V ~ith compounds of the formula VI
R300C-~C -N~H ~OOC~ CH ( H2)n~R
(V) (VI)
The reaction of these compounds can, ~or example, be
carried out in analogy to kno~n peptide coupling pro~
cesses in the presence of coupling auxiliaries such as
carbodiimides ~for examPle dicycLohexylcarbodiimide),
diphenylphosphoryl azide, alkanephosphoric anhydrides,
dialkylphosphinic anhydrides or N~N-succinimidyl car-
bonates in CH3CN. Amino groups in compounds of ~he
formula V can be activated ~ith tetraethyl diphosphite.
The compounds of the formula VI can be converted into
.

1 320qO4
_ 9 _
active esters ~for example ~ith 1-hydroxybenzotri-
azole), mixed anhydr;des (for example with chloroformic
esters), azides or carbodiimide derivatives, and thus
be activated (cf. Schroder, LBbke, The Peptides, Vol.
1, New York, 1965, pages 76 136).
It is likewise possible to react compounds of the for-
mula YII ~ith compounds of the 70rmula VIII, ~ith the
formation of compounds of the formula I
R OOC-ICH-~ - C IM-~ Y~ lH t H2)n-R
O R OOR
(V~I ) ('VIII )
in ~hich either y1 represents amino and y2 represents
a leaving group, or y1 represents a leaving group and
y2 represents amino. Examples of suitable Leaving
groups are Cl, ar, I~ alkylsulfonyloxy or arylsulfonyl-
oxy .
Alkylations of this typB ~re advantageous~y carried outin water or an or~anic solvent, in the presencs of a
base.
Furthermore, compounds of the for~ula IX san be con-
densed ~ith co~pounds of the formula X
R300C_~H_ _ c~ l Q2~f -lC 2)~-R
0 R C~R
~IX) (X3
in ~hich either ~1 represents amino 4 hydrogen and ~2
represents oxo, or Q1 represents oxo and ~2 represents
amino + hydrogen
The condensation is advantageously carried out ;n ~ater

'I 320qO4
- 10 -
or an organic solvent such as a lo~er alcohol, and ;n
the presence of a reducing agent such as Na8H3CN,
whereupon compounds of the formula I are obtained dir-
ec~ly. However, ;t ;s also possible to reduce the
Schiff's bases or enamines ~hich result as intermedi-
ates~ ~here appropriate after previous isolation, with
the format;on of compounds of the formula I, for exam-
ple by hydrogena~;on in the presence of a transi~ion
metal catalyst.
Finally, reaction of compounds of the f~rmula IX (a1 =
H + N~2) w;th compounds of the formula XI, or their
reaction with compounds of the for~ulae XII and XlII,
also results in compounds of the formula I (n=2)~ !
R~OC-C~-CH-~O-R
~XI~
OCH-CO~R2 R-CO-~H3
tXII) (XIII)
there being reduction of Schi~f~s bases produced as
intermediates, and conversion of a carbonyl group into
nethrlene by reduction.
In the above~entioned formulae V-XIIl, R-RS and n are
as de~ined in formula I. Protective groups introduced
temporarily to protect reactive groups not involved in
the reac~;on are elim;nated a~ter reaction is complete
in ~ manner known per se (cf. Schroder, Lubke~ lOca
cit., pages 1~7S and 246-270)~
It is possible and part;cularly advantageou~ to use the
follo~ing co~pounds in the ~ethod according to the in-
vention:
N~ S-carboethoxy-3-phenylPropyl~-s-alanyl-s-1~2~3~4
tetrahydroisoquinoline-3-sarbQxylis acid

1 320904
- 11 -
N-tl-S-carboethoxy-3-cyc~ohexylpropyl)-S-alanyl-S-
1~2,3,4-tetrahydroisoquinoline-3-carboxylic acid
N-(1-S-carboethoxy-3-phenylpropyl)-S-Lysyl-S-1~2,3,4-
tetrahydroisoquinoline-3-carboxylic acid
N-(1-S-carboethoxy-3-phenylpropyl)-0-e~hyl-S-~yrosy(-
S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
N-(1-S-carboethoxy-3-phenylpropyl~-S-alanyl-3S-deca-
hydro-isoquinoline-3-carboxylic acid
H-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-
(2S~3aS,7aS)-octahydroindole-2-carboxylic acid
N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-
(2S,3aS~7aS)-octahydroindole-2-carboxylic acid
N-(1-S-carboethoxy-3-phenylpropyl)-S-lysyl-(2S,3aS,7aS)-
octahydroindole-2-carboxylic acid
N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-lysyl-
(2S,3aS,7aS)-octahydroindole-2-carboxylic acid
N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-lysyl-
(2S,3aS,7aS)-octahydroindoLe-2-carboxylic acid
N-(1-S-carboethoxy-3-phenylPropyL)-0-methyl-S-tyrosyl-
(25,3aS,7aS)-octahydroindole-2-carboxylic acid
N-t1-S-carboethoxy-3-phenylprop~l)-0-ethyl-S-tyrosyl
(2S,3aS,7aS)-sctahydroindole-2-carboxylic acid
N-t1-S-carboethoxy-3-~3,4-d;methylphenylpropyl)-S-
al3nyl-tZS,3aS,7aS)-oetahydroindole-2-carboxylic acid
N-~1-S-carboethoxy-3-(4-fluorophenyl~-propyl]-S-alanyl-
~2S,3aS,7aS)-octahydroindole-2-carboxylic acid
N-t1-S-carboethoxy-3-~4-~ethoxyphenylj-propyl~-S-alanyl-
(2S,3aSJ7aS)-octahydroindole-2-carboxylic acid
N-C1-S-carboethoxy-3-(3,4-dimethoxyphenyl)-propyl]-S-
alanyl-~2S,3aS~7aS)-octahydroindole-2-carboxylic acid
N-(1-S-carboethoxy-3-cyclopentylpropyl)-S-alanyl-
~2S,3aS,7aS)-octahydroindole-2-carboxylic acid
N-t1-S-carboethoxy-3-phenylpropyl)-S-alanyl-
~2S,3aR,7aS)-octahydroindole-Z-carbo~ylic ~cid
N (1-S-carboethoxy-3-cyclohexylPropyl3-S-alanyl-
(2S,3aR,7aS~-octahydro;ndole-carboxylic acid
N-(1-S-carboethoxy-3-phenylpropyl)-S lysyl-~2S,3aR~7aS)-
octahydroindole-2-carboxylic acid

1 320904
- 12 -
N-(1-S-carboethoxy-3-cyclohexylpropyl)-5-lysyL-
(2S,3aR,7aS)-octahydroindole-2-carboxylic acid
N-(1-S-carboethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl-
(?s~3as~7aR)-octahydro;ndole-2-carboxylic acid
N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-
(2S,3aR~7aR)-oc~ahydroindole-2-carboxylic acid
N-(1-S-carboethoxy-3-phenylpropyl)-S-lysyl-(2S,3aR,7aS)-
octahydroindoLe-2-carboxylic acid
N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-
1D (2S,3aR~7aR)-octahydroindole-2-carboxylic acid
N-(1-S-c~rboe~hoxy-3-cyclohexylpropyl)-0-ethyl-S-tyro-
syl-~2S,3aR,7aR)-nctahydroindole-2-carboxylic acid
N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-
(25~3aS,7aR)-octahydroindole-2-carboxylic acid
N-(1-S-carboethoxy-3-phenylpropyl~-0-ethyl-S-tyrosyl-
(ZS,3aS,7aS)-octahydroindole-2-carboxylic acid
N-(1-S-carboethoxy-3~4-dimethylphenylpropyl3-S-alanyl-
(2S,3aS,7aS)-octahydroindole-2-carboxylic acid
N-E1-S-carboethuxy-3-(4-fluorophenyl)-propyl~-S-alanyl-
t2S,3aS,7aS)-octahydroindole-2-carboxylic acid
N-~1-S-carboethoxy-3-(4-~ethoxyphenyl)-propyl]-S-al3nyl-
(2S,3aS,7aS)-octahydroindole-2-carboxylic acid
N-C1-S-carboethoxy-3-5394-dimethoxyphenyl)-propyl]-S-
alanyl-(2S,3aS,7aS)-octahydroindole-~-carboxylic acid
N-(1-S-carboethoxy-3-cyclopentylpropyl)-S-alanyl-
: (2S,3aS~7aS)-octahydroindole-2-carboxyl;c acid
N-(1-S-carboethoxy 3-phenylpropyl)-S-alanyl-cis-endo-2-
azabicyclo~3~3.0]octane-3-S-carboxylic acid
N-(1-S-carboeth3xy-3-phenylpropyl)-S-lysyl-cis-endo-2-
azabicycloC3.3.0~octane-3-S-carboxylic acid
N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-cis-
endo-2-azabicycloC3.3.0~oct~ne 3-S~carboxylic acid
~-51-S-carboxy-3-cyclohexylpropyl)-S-alanyl-cis-Lndo-2-
azabicyclo~3.3.0~octane-3-S-carboxylic acid
N-~1-S-carboethoxybutyL)-S-alanyl-cis-endo-2-azabicycLo-
C3.3~0~oct~ne-3-S-carboxylic acid
N-l1-S-carboethoxy-3-(3~4-di0ethoxyphenylpropyl)-S-aLanyl-
cis-endo-2-azabicyclot3.3aO]ost3ne-3-S-carboxylic acid

1 320904
- 13 -
~ S-carboethoxy-3-cyclopentylpropyl)-S-alanyl-cis-
endo-azabicyclo-C3.3.0]octane-3-S-carboxylic acid
N-(1-S-carboethoxy-3-phenylpropyl) 0-methyl-S-tyrosyl-
S cis-endo-2-azabicyclo~3.3.0~octane-3-S-carboxylic acid
N-(1-S-carboethoxy-3-phenylpropyl)-0-ethyl-5-tyrosyl-
cis-endo-2-azabicyclot3.3.03Octane-3-S-carboxylic acid
N-(1-S-carboethoxy-3-(4-fluorophenylpropyl)-S-alanyl-
cis-endo-azab;cyclo~3.3.0]octane-3-S-carboxylic acid
N-(1-S-carboethoxy-3-(4-methoxyphenylpropyl)-S-alanyl-
cis-endo-2-azabicyclo~3.3.0]octane-3~5-carboxylic acid
N-(1-S-carboethoxy-3-phenylpropyl)-S-lysyl-(2S,3aR,6aS)-
octahydrocyclopenta~b~pyrrole-2-carboxylic acid
N~ S-carboethoxy-3-cyclohexylpropyl)-lysyl-(2S,3a,6aS)-
octahydrocyclopentatb3pyrrole-2-tarboxylic acid
N-(1-S-carboethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl-
(2S,3aR,6aS)-octahydrocyclopenta~b~pyrrole-2-carboxylic
acid
N-(1-S-carboethoxy-3-phenylpropyl)-S-a~anyL-2-
Z0 (2S,3aR,6aS)-octahydrocyclopen~atb~pyrrole-2-carboxyl;c
acid
N (1-S-carboethoxy-3-phenylpropyl)-S-alanyl-2-azaspiro-
t4~5]decane-3-S-carboxylic acid
N-~1-S-carbo~thoxy-3-phenylpropyl)-0-ethyL-2-tyrosyl-
azaspiro-C4~5~decane-3-S- arboxylic acid
N-(1-S-carboethoxy-3~phenylpropyl)-S-lysyl-2-azaspiro-
E4.53decane-3-S-carboxylic acid
N-(1-S-carboethoxy-3-cyclohexylpropyL)-S-alanyl-~-aza-
spiro~4.5~d2cane-3-S-carboxylic ac1d
N-t1-S-carboethoxy-3-cyclohexylpropyl)-S-lysyl-2-aza~
spiroC4.5~decane-3-S-carboxylic acid
N-(1-S-c2rboethoxy-3-phenylpropyl)-S-alanyl-2-azaspiro-
C4.4~nonane-3-S-carboxylic acid
N-(1-S-carbo~thoxy~3~Phenylpropyl)-o-ethyl-s~tyrosyL-2
azaspiro~4.4~nonane-3-S-carboxylic acid
N-(1-S-carboethoxy-3-phenylpropyl)-S-lysyl 2 azaspiro-
t4.4~non3ne-3-S-carboxylic acid
N-t1-S-carbo~thoxy-3-cyclohexylpropyl)-5-alanyl-2-aza-
spiro[4.4~nonane-3~S-carboxylic acid

I 320904
- 14 -
N-(l-S-carboethoxy-3-cyclopentylpropyl)-S-alanyl-2
azaspirot4.4~non3ne-3-S-carboxylic acid
N-t1-S-carboethoxy-3-cyclopentylpropyl)-S-lysyl-2-aza-
spirol4.4]nonane-3-S-carboxylic acid
N-51-S-carboethoxy-3-phenylpropyl)-S-alanyl-spiro-
tbicyclo~2.2.1]heptane-2,3'-pyrrolidine~-5'-S-carboxylic
acid
N~ S-carboethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl-
spiroCbicyclol2.2.1]heptane-2,3'-pyrrolidine~-5'-S-
carboxylic acidN-(1-S-carboe~hoxy-3-phenylpropyl3-S-lysyl-sp;ro-tbicyclo
t2.201~heptane-2~3'-pyrrolidineJ-S'-S-carboxyiic acid
N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-spiro-
Cbicyclo~2.2~1~heptane 2,3'-pyrrolidine3-5'-S-carboxy-
lic acidN-t1-S-carboethoxy-3-cyclohexylpropyl)-S~lysyl-spiro~
tbicyclo~2.201~heptane-2,3'-pyrrolidine3-S'-S-carboxy-
l;c ac;d
N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-spiro-tbi-
cyclot2.2.Z~octane-2,3'-pyrrolidine]-S'-S-carboxylic
acid
N-(1-S-carboethoxy-3-phenylpropyl)-0-ethyl-tyrosyl-
~piro~bicyclot2.2.2~octane-2,3'-pyrrolidine~-5'-S-
carboxylic acid
N-(1-S-carboethoxy-3-phenyLpropyl)-S-lysyL-spiro~bi-
cycloC2.2.2]octane-2,3'-pyrrolidine~-5'~S-carboxylic
acid
N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-spiro-
CbicycLo~2.2.2]o&tane-2,3'-pyrrolidine]-S'-S-carboxylic
acid
N~ S-sarboethoxy-3-ph~nylpropyl)-S-alanyl-2-azatri-
cyclo~4.3Ø16'9~decane-3-S-carboxyl;c acid
N-(1-S-carboethoxy-3-phenylpropyl~-0-ethyl S-tyrosyL-
2-azatricyclo~4.3Ø1~'9]decane-3 S-carboxylic acid
N-~1-S-carboethoxy-3-PhenylPropyl)-S-lysyl-2-azatri-
cycloC4.3Ø16'~idecane-3 S-carboxylic acid
N-t1-S-carboethoxy~3-cyclohexylPropyl)-s-alanyl-2
azatricyclo[4.3Ø16'9~decane-3-S-carboxylic acid

1 320904
- 15 -
N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-lysyL-2-aza-
tricycLo~4.3Ø16'9]decane-3-S-carboxylic acid
N-(1-S-carboethoxy-3-phenyLpropyla-S-alanyl-decahydro-
cycloheptalb]pyrrole-2-S-carboxylic acid
N-(1-S-carboethoxy-3-phenylpropyL)-0-ethyl-S-tyrosyl-
decahydrocyclohepta[b]pyrrole-2-S-carboxylic acid
N-(1-S-carboethoxy-3-phenylpropyl)-S-lysyl-decahydro-
cyclohepta~b3pyrrole-2-S-carboxylic acid
N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-deca-
hydrocyclohepta~b]pyrrol~-2-S-carboxylic acid
N-(1-S-carboethoxy-3-cyclo~exylpropyl)-S-lysyl-deca-
hydrocycloheptaLb]pyrrale-2-S-carboxylic acid
N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-trans-octa-
hydroisoindole-1-S-carboxylic acid
N-(1-S-carboethoxy-3-phenylpropyL)-S-alanyl-cis-octa-
hydroisoindole-1-S-carboxylic ac;d
N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-trans-
octahydro;soindole-1-S-carboxyLic acid
N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-cis-
octa-hydroisoindole-1-S-carboxylic acid
N-t1-S-carboethoxy-3-phenylpropyl)-S-alanyl-cis octa-
hydrocyclopentaCc]pyrrole-1-S-carboxylic acid
N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-aLanyl-cis-
octahydrocyclopentatc~pyrrole-1-S-carboxylic acid
benzyl ester
N-(1-S-c~rboethoxy-3-cyclohexylpropyl)-S-lysyl-cis-octa-
hydrocyclopenta~c~pyrrole-1-S-carboxylic acid
N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-2,3,3a,4,5,
~a-hexahydroindole-cis-endo-2-S-carboxylic ~cid
0 N-(1-S-carboethoxy~3-phenylpropyl~-S-lysyl-2,3,3a,4,5
7a-hexahydroindol?-cis-endo-2-S-carboxylic acid
N-(1 S-carboethoxy-3-cyclohexylpropyl)-S-lysyl-2~aza-
bicyclQ~3.1.D~hexane-3-S-carboxylic acid
N-(1-S-c~rboxy-3-phenylpro~yl~-S-lysyL-2-azabicyclo-
C3.1.0~hexane-cis-endo-3-S-carboxyLic acid
N-(1-S-carboethoxy~3-cyclopentylpropyl)-S-alanyl-2--aza-
bicyclot3~1.0~hex~ne-3-carboxylic acid
N-(1-S-carboethoxy-3-phenrlpropyl~-S~alanyL-cis~endo-2-

1 320~0~
~ 16 -
a~abicycloC3.1.0]hexane-3-S-cArboxylic acid
N-(1-S~carboethoxy-3-cyclohexyLpropyl)-S-alanyl-cis-
endo-2-azabicycLo~3~1.o]hexane-3-s-carboxylic acid.
These compounds can be prepared by, for example, the
process described in German Patent Application P
3,333,455.2, in which process the tsrt.-butyl or benzyl
esters described in the application are converted
into the monocarboxylic acid derivatives in known man-
ner by acid or alkaLine hydrolysis or by hydrogenolysis
catalyzed by noble met~ls. The N-benzyloxycarbonyl
protective group of ~he lysine derivatives is removed
by hydrogenolysis catalyzed by noble m~tals~ The com-
pounds listed above can be readily converted ~ith
physiologicaLly tolerated acids or bases (in the czse
of mono- or d;carboxylic acids) into the corresponding
salts (for exa~ple hydrochlorides, maleates, fumarates
etc.) and be used as salts zccording to the invention~
The compounds of the formula I are inhibitors of angio-
tensin converting enzyme (ACE) or intermediates in the
preparation of s~ch inhib;tors, and they can also be
used to control high blood pressure of various etiolo-
gies. The compounds of the formula I are disclosed in,
for exa~ple, US Patent 4,129,571, US Patent 4,374,829,
European ~atent A-79,522, Furopean Patent A-7~,022,
European Patent A-49,658, European Patent A-51,301~ US
Patent 4,454,292, US Patent 4,374,847, European Patent
A-72,352, US Patent 4,35U,704, European Patent A-50,8Q0,
European Patent Ao46,~53, US Patent 4~344,949, European
Patent A-84~164, US Patent 4,470,972, European Patent
A-65,301 and European Patent A-52,991.
Also advantageous are or~lly effective ACE inhibitors
such as, for exam~le, ra~ipril, enalapril, t~ptopr;l,
lisinopril, perindopril, cilazapril, RHC 3659, CGS
13945, CGS 13928C, CGS 14B24A~ CI-9D6, SCH 31846~
zofenopril~ fosenopril~ alacepril and others. Orally

1 ')2090~
- ~7 -
effective ACE inhibitors are described in, for example,
~runner et al., J. Card;ovasc. Pharmacol. 7 (Suppl. I)
(~985) S2-S11.
Preferred ACE inhibitors are ~hose disclosed in Europ-
ean Patent d-79022, of the formula III
C~ ~S) ~S~ (III)
H N~ C~2 ~ I H~
O CH3 ~00R
in ~hich R denotes hydrogen, ~ethyl, ethyl or benzyl,
in particular the compound o~ the ~ormula III in which
R denotes ethyl (ramipril).
Other preferred ACE inhibitors are those disclosed in
European Patent A-84~164, of the formula IV
B
COOH (IV)
~ N~ ~S9 IS) ~r-~
O ~ q ~H - C~ CH2 o G~2
~3 ~ooR4 o
in ~hich R4 denotes hydrogen, (C1-C4~-alkyl or benzyl,
in particular the compound of the formula IV~ in ~hich
R4 denotes ethyl.
In carrying out the method according to the invention,
the angiotensin conYerting enzyme inhibitors described
above can be admini tered to mammals such as ~onkeys,
dogs, cats, rat~, humans etc. The compounds ~hich are
suitable for the use according to ~he invention are ad-
vantageou~ly incorporated in pharmaceutical products incustomary manner~ They can be converted into the CU5-
tomary administratiDn forms, such as capsules, tablets,
coa$ed tablets~ solutioQs, oint~ents and emulsions, as
weLl as into a depot form. The active compound can~

~ 320904
~here appropriate, also be in microencapsulated fc~rm.
The products can contain additional, tolerated organic
or inorgan;c substances, for example granulating auxi-
liaries~ adhesives and b;nders, lubr;cants, suspend;ng
agents, solvents, antibacterial agents, ~ett;ng agents
and preservatives~ Forms for oral and parenteral ad-
ministration are preferred. ~he compounds of the
formula l can be administered in dosages of 0.1-50 mg
per dose once to three times a day.
It is also poss;ble according to the invention to use
the ACE inhibitors in combination wi~h substances ~hich
influence prostaglandin met~bolis~. Examples of such
substances are stable prostacyclin analogs, inhibi~ors
of thromboxane synthetase, and thromboxane an~agonists.
Hence the invention also reiates to pharmaceuticaL com-
positions containing a) an AC inhibitor or ies physio-
logically tolerated salt and b) a substance ~hich
influences prostaglandin metabolism or its physiologi-
cally tolerated salt, and to ~he;r use for the treat-
ment of atherosclerosis~ of thrombosis and/or ofperipheral vessel dis~ase.
The invent1on furthermore relates quite generally to
products containing the substances mentioned above
under a~ and b~, as combination products for conçur-
ZS rent~ separate or sequential administration for thetreatment of atherosclerosis, of thr~mbos;s and/or of
peripheral vessel disease.
An increased a~gregability of the blood platelets plays
a particularly important part in the development of
atherosclerosis. Examples of sequelae are thromboses
and peripheral vessel d;sease; these d;seases are the
main cause of the incr~ased morbidity and mortality
a sociated with high blood pressure~ alood platelets
cont3in an anyiotensin-I-processin~ system, and their

1 ~20904
- 19 -
membrane has binding sites ~ith high affinity for
angiotensin II. The fact that angiotensin converting
enzyme (ACE) is preponderantly located on the luminal
cytoplasmic membrane of the endo~helial cells points to
S platelet/endothelium interactions being associated
~ith local angiotensin II produc~ion; ACE ;nh;bitors
can ;nterfere ~;th this Furthermore, inh;bit;on of
ACE poten~iates the action of bradykinin by preventing
;ts breakdo~n. It is known tha~ bradykin;n is a potent
stimulator of the release of prostacycl;n from endo-
theliai cells; bradykinin is in turn a potent ;nhibitor
of platelet aggregation.
The activ;ty of the compounds of ~he for~ula I on
platelet aggregation and thus on atherosclerosis,
thrombosis and peripheral vessel disea~e, as well as
other disease states associated ~;th ;ncreased aggreg-
ab;lity of the blood platelets, can be deduced from a
variety of test model~.
In each of the examples ~hich follow use is made of the
results ~ith N~ S-carboethoxy-3-Phenylpropyl)-s-
alanyl-cis-endo-2-azabicyclo~3.3.û~octane-3-S-carboxylic
acid (Formula II~.
.
~,COOH
g) E~H-~H - C~-CH2 - CH2~ II
I~H3 ~ 2C2H5
A In vitro results
Platelet-rich rabbit pl~s~a ;s obtained as stated by
~orn tArzneimittel-Forsch~ 31, 2012 (1~81)). Platelet
aggreg3tion is measured by the increase in light pass-

1 320qO4
- 20 -
ing through a ceLl ~hich contains this plasma. The
pla~elet count is adjusted to 450,000/mm3 by dilut;on
~ith autologous, platelet-poor plasma. The sompound of
the formula II has, in concentrat;ons of 0.1-10 ~g/ml
of plasma, no effect on the aggregation induced by 0.24
mmol/l arachidonic aciJ, 5 mmol/l ADP or 4 ~g/ml colla-
gen. In contrast, the inh;bition, brought about by 4
~g/ml PGI2, of aggregation caused by arachidonic acid
is increased to 100% by the compound of the formula II
in the said dose range.
8 l~ vi~
1. Acute study
.
Conscious rabb;ts received a single oraL dose of
1.0-10.0 mg/kg of the co~pound o~ the formula II.
After 1 hour, the animals are sacrificed, and
platelet-rich plasma is obtainedO Platele~ aggreg-
ation is determined as describ~d under A).
There is fsund to be a reduction in aggregation in
response to the three stimulators described there,
in particular in response to ~rachidonic acid. A
potenti3tion of the PGI2 effect is also observed.
2. Chronic study
Conscious rabbits received 1 mg/kgtd of the compound
of the formula IE for 14 days~ and then the proce-
dure was continued as described under 1). Pro-
nounted inhibition of the platelet aggregation
induced by ~rachidonic acid and A~P is ~ound in all
animals.
The examples ~hich follo~ indicate the forms ~or admin-
istration to treat atheroscl~rosis, thrombosis and
peripheral vessel d;seas4 by the method according to

1 320904
- 2~ -
the invention. The compounds of the formula I can be
converted into the corresponding forms for adminis-
traeion in analogy eO the examples.
Exam
Preparation of the a~ent used according ~o the inven-
tion for oral adm;nistrat;on in the treatment of
atheroscLerosis, of thrombosis and of peripheral vessel
diseaseO
1000 table~s each containing 10 mg of 1-N-(1-S-carbo-
ethoxy-3-phenylpropyl)-S-alanyl-1S,3S,5S-2-azab;cycLo-
C3.3.0]octane-3-carboxylic acid are prPpared ~ith the
following auxiliaries:
N-(1-S-carboethoxy-3-phenypropyl)-S-alanyl-
1S~35,5S-~-azabicycloC3~3.0]octane-3-
carboxyliç acid 10 9
rorn starch 140 9
6elatine 7~5 ~
Microcrystalline cellulose 2.5 9
Magnesium stearate 2~5 9
N~ S-carboethoxy-3-phenylpropyl)-S-alanyl-15,3S,5S-
: 2-azabicyclot3.3.0]octane-3-carboxylic acid and corn
starch are mixed ~ith an aqueous gelatine solution.
The mixture is dried and milled to granules. Micro-
crystalline cellulose and magnesiu~ steara~e are mixed
~ith the granules. The resultin~ granules are cDm-
pressed to form 1300 table~s, each tablet containing 10
~g of the ACE inhibi~or.
These tablets can be us~d ~or the treatment o~ a~hero-
sclerosis~ of thrombosis and/or of peripheral vessel
3D disease.

1 32090~
- 22 -
Example 2
~ .
1000 tablets each conta;n;ng 10 mg of N~ S-carbo-
ethoxy-3-phenylpropyl~-S-alanyl~2S,3aR,7aS)-octahydro-
;ndole-2-carboxylic acid hydrochloride are prepared in
analogy to Example 1.
Example 3
6elat;ne capsules each containing 10 mg of N-(1-S-
carboethoxy-3-phenylpropyl)-S-alanyl-1$,3S,5S-2-aza-
b;cycloC3.3.5]octane-3-carboxylic acid are filled ~ith
lD the foLlo~ing ~ixture:
!
N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-
1$,3S,SS-2-azabicyclo~3~3.0~octane-3-
carboxyl;c acid 10 mg
Magnesium stearate 1 mg
Lactose 214 mg
These capsules can be used for the treatment of athero-
sclerosis, of thrombosis and/or o~ peripheral vessel
diseaseO
Example 4
. .
2U The preparation of an injection solut;on for the treat-
~ent of atherosclerosis, of thrombosis and/or of peri-
pheral vessel disease is de-~cribed below:
N~ S-carboxy-3-phenylpropyl)-S-alanyl-
15,3S95S-2-azabicycloC3.3.0~octane-3-
carboxylic acid 250 mg
~ethylparaben 5 9
Propylparaben 1 9
Sodiu~ chlorîde 25 9
~ater for injections 5

1 3'20qO4
- 23 -
N-(1 S-carboxy-3-phenyLpropyl)-S-alanyl-lS,3S~SS-Z-
azabicyclot3.3.0~octane-3-carboxylic acid, the preser-
vat;Yes and sodium chloride are dissolved in 3 l of
~ater for injections, and the solution is made up to 5
L ~ith water for injections~ The solution is filtered
sterile, and d;spensed aseptically into presterilized
bottles, which are closed ~ith s~erilized rubber caps.
Each bottle contains 5 ml of solution.
Example 5
Tablets which can be used for ~he treatment of athero-
sclerosis, o~ thrombosis and/or of peripheral vessel
disease are prepared as described in Example 1, ~ith
the exception that in place of N-t1-S-carboethoxy-3-
phenylpropyl)-S-alanyl-15,3S,SS-Z-azabicycloC3.3.0]-
uc~ane-3S-carboxylic acid
N-f1-S-carboxy-3-phenylpropyl)-S-alanyl-1S~35,5S-2-
azabicyclo~3.3.0]octane-3-carboxy~;c acid or
H-(1AS-carboxy-3-phenylpropyl~-S-alanyl-2S,3aR,7aS-
octahydroindole-2-carboxylic acid or
N-(1-S-carboethoxy-3-phenylprspyl)-5-3lanyl-cis-
2"3,3a,4~5f7a-hexahydro~1H~indole-~-S-endo-carboxylic
acid or
N (1-S-carboxy-3-phenyLpropyl)-S-alanyL-cis-2,3,3a,4,
5,7a-hexahydro~1H~indole-25-endo-carboxylic ac;d or
N-(1-S-carboxy-3-phenylpropyL)-S-lysyl-1S,3S,5S-2-
a~abicyclo~3.3.0~octane-3-carboxylic acid or
N-~1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyL-
1S,3S,5S-2-azabicyclor3.3.0]octane-3-carboxylic acid or
N-~1-S-carboxy-3-cycLohexyLpropyl)-S-lysyl-1S~3S,5S-2
azabicyclo[3.3.0]octane-3-carboxylic acid are used.
Example 6
An injection solution is prepared in analogy to the
procedure described in Example 4, ~ith thP excep~ion
that in pLace of N-(1-s-carboeehoxy-3-phenylpropyl)

1 320904
- 24 -
alanyL-1S,3S,5S-2-azabicyclo[3.3.0]octane-3-carboxylic
acid
N-t1-S-carboxy-3-phenylpropyl)-S-alanyl-lS,35,5S-2-
azabicyclor3.3.0~octane-3-carboxyl;c acid or
N-(1-S-carboethoxy-3~phenylpropyl)-S-al~nyl-2S,3aR,7aS-
octahydroindole-2-carboxylic acid hydrochloride or
N-~1-S-carboxy-3-phenylpropyl)-S---alanyl-25,3aR,7aS-
octahydroindole-2-carboxylic acid or
N-(1-S-carboethoxy-3-cyclohexylpropyl3-S-al~nyl~cis-
2,3,3a~4,5,7a-hexahydroC1H]indole-2-S-endo-carboxylic
acid or
N-(1-S-carboxy-3-phenylpropyl)-S-alanyl-c;s-2,3,3a,4,5,
7a-hexahydroC1H]indole-2-S-endo-carboxylic acid or
N-(1-carboxy-3-phenylpropyl)-S-lysyl-1S,3S,5S-2-aza-
bicycloC3.3.0~octane-3-carboxylic acid or
N~ S-carboethoxy-3-cyclohexyl)-S-alanyl-15,3S,5S-2-
azabicyclot3.3.0]octane-3-carboxylic acid or
N-~1-S-carboxy-3-cyclohexylpropyl)-S-lysyl-1S,3S,5S-2-
azabicyclot3.3.D~octane-3-carboxylic acid are used.